ArticleThe EMBO journal2021
Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.
Article in The EMBO journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 15 citations in OpenAlex.
- MSK1 mediates BDNF-dependent MeCP2-S421 phosphorylation in postnatal striatal development and psychiatric-relevant behaviours.Molecular psychiatry · 2026Article
- Translational Relevance of SCA1 Models for the Development of Therapies for Spinocerebellar Ataxia Type 1.Biomedicines · 2025Review
- pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex ofProceedings of the National Academy of Sciences of the United States of America · 2025Article
- A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning.The Journal of pathology · 2025Article
- pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex ofbioRxiv : the preprint server for biology · 2024Article
- ZBTB7B is a permissive regulator of hepatocellular carcinoma initiation by repressing c-Jun expression and function.Cell death & disease · 2024Article
- Dysregulation of alternative splicing in spinocerebellar ataxia type 1.Human molecular genetics · 2024Article
- Therapeutic Strategies for Spinocerebellar Ataxia Type 1.Biomolecules · 2023Review
- Identification of risk genes for Alzheimer's disease by gene embedding.Cell genomics · 2022Article
- Article
- The extra-cerebellar effects of spinocerebellar ataxia type 1 (SCA1): looking beyond the cerebellum.Cellular and molecular life sciences : CMLS · 2022Review
- Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1.The Journal of clinical investigation · 2022Article
- Reduction of mutant ATXN1 rescues premature death in a conditional SCA1 mouse model.JCI insight · 2022Article
- Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1.The EMBO journal · 2021Article
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
Abstract
A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem-the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.